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<blockquote data-quote="madman" data-source="post: 267306" data-attributes="member: 13851"><p>Chances are slim, especially at your age.</p><p></p><p>Both would be used for the long-term as T levels will go back to baseline when you stop.</p><p></p><p>There is a small percentage of men who may respond to a short trial of clomiphene citrate to reboot the HPTA.</p><p></p><p>Younger men tended to do better.</p><p></p><p>Even then long-term high-quality RCTs on clomid/rebooting the HPTA are lacking.</p><p></p><p>Most giving clomid/hCG mono a go ends up jumping on TRT in the long run.</p><p></p><p></p><p></p><p></p><p>Key points here:</p><p></p><p><strong><em>*We hypothesize that <u>MH is a chronic irreversible condition in most cases, but in a selected group of patients</u>, which Devoto and Aravena call mild hypothalamic dysfunction, <u>a trial with CC could reboot the HPT axis</u></em></strong></p><p><strong><em></em></strong></p><p><strong><em>*Our study has some limitations worth discussing. <u>About 40% of the subjects initially screened did not finish the follow-up and were excluded, of whom 40% kept symptomatic and 60% elected to change to testosterone therapy</u>; however, this represents the real-life challenges that must be accounted for</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*Based on current results, <u>one in every four hypogonadal men with normal testicles may respond to a short trial of CC to "reboot" the HPT axis, with the potential for physiology maintenance, avoiding chronic treatment. Responders tend to be younger patients</u></em></strong></p><p><strong></strong></p><p><strong>*<em>CC is a compelling option to treat male hypogonadism, <u>although a chronic treatment is needed in most patients</u>. <u>About one in every four patients respond to a CC short trial to "reboot" the HPT axis physiology</u>. <u>Further understanding of TT kinetics in these patients in the long term is warranted</u></em></strong></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/clomid-monotherapy-to-treat-male-hypogonadism-chronic-treatment-is-needed-in-most-patients.25319/[/URL]</p><p></p><p><strong><em>*The main objective of our study was to elucidate which percentage of MH reversed by a 40-day CC treatment can sustain physiological TT levels in the midterm since scarce studies analyzed the kinetics of TT after stopping CC treatment.</em></strong></p><p></p><p><em>Kaminetsky et al. reported that in patients with secondary hypogonadism who responded to enclomiphene citrate therapy, once the treatment was stopped, TT levels decreased and returned to the pre-treatment values [11]. The same happened in the Marconi et al. study, which reported decreased TT levels 3 months after discontinuation of CC treatment, 78% under the normal range. The six cases in which TT was in the normal range 3 months after CC discontinuation also dropped TT levels (to pre-treatment levels) 6 months after ending treatment [4].</em></p><p><em></em></p><p><em>Devoto and Aravena reported contrasting results in a subgroup of patients with functional hypogonadotropic hypogonadism who respond to CC therapy by maintaining normal TT levels 6 months after ending treatment [12]. Our study partially agreed with their data; 18 patients (24%) maintained asymptomatic and with TT levels over 300 ng/dl after 6 months of stopping the treatment, against the 12/16 (75%) of Devoto. This conflict could be due to the study draw since they just analyzed the patients who responded to a 10-day trial with CC and used a 6-month CC therapy. <strong>We hypothesize that MH is a chronic irreversible condition in most cases, but in a selected group of patients, which Devoto and Aravena call mild hypothalamic dysfunction, a trial with CC could reboot the HPT axis.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>On behalf of drug safety and side effects, a long-term follow-up cohort demonstrates that CC is an oral therapy with durable efficacy and a favorable side effect profile in the long term up to 7 years. </strong>Only 36 men (9%) reported side effects in that cohort, the most common side effects were consistent with those reported in prescribing information.<strong> However, patients and providers should also be aware of the progressive need to monitor for symptoms of hyperestrogenemia while on sustained CC therapy [10].</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Molecular studies show that CC is composed of two very different isomers, <u>enclomiphene (EC), the trans-isomer (62%), and zuclomiphene, the cis-isomer (38%)</u>—with potentially opposing effects. The first isomer has an estrogen antagonist effect, by preventing estrogen receptor-mediated negative feedback at the level of the pituitary and hypothalamus, while zuclomiphene acts as an estrogen agonist [13]. <u>The trans-isomer is a very promising drug for MH, appearing to be responsible for the desired anti-estrogen effect of CC, offering significant elevations in T levels</u> [11, 14].</strong></em></p><p><em><strong></strong></em></p><p><em><strong>This could result in the correction of testosterone levels and hypogonadal symptoms without suppressing spermatogenesis.<u> In addition to the benefits mentioned above, enclomiphene lacks the estrogen receptor agonist activity seen with clomiphene citrate caused by the cisisomer zuclomiphene, which accumulates in the body and can take more than 6 months to be eliminated after discontinuation of treatment</u>.</strong> <strong><u>This may mitigate some of the estrogenic side effects that some men can present and increase the potential beneficial effects</u> [14, 15]. Unfortunately, due to the difficulty inherent in getting a new molecular entity approved by the FDA, the future of enclomiphene looks bleak at best [16].</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Our study has some limitations worth discussing. About 40% of the subjects initially screened did not finish the follow-up and were excluded, of whom 40% kept symptomatic and 60% elected to change to testosterone therapy; however, this represents the real-life challenges that must be accounted for.</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong><u>Based on current results, one in every four hypogonadal men with normal testicles may respond to a short trial of CC to "reboot" the HPT axis, with the potential for physiology maintenance, avoiding chronic treatment</u>. <u>Responders tend to be younger patients</u></strong>. Baseline gonadotropins were not strong predictors of CC treatment response in hypogonadal men [2], thus not evaluated in our study.</em></p><p></p><p><strong><em>A recent meta-analysis comprising 17 studies (four randomized controlled trials), with a total of 1279 patients has shown significant hormones, semen, and symptoms improvement in hypogonadal men during CC treatment, with<10% adverse events reported (none serious) [17]; <u>however, more extensive prospective trials are needed to understand further the durability of the hormonal response to CC with time</u>.</em></strong></p><p></p><p><em><strong>While little is known about CC’s effect on the intercellular signaling and testicular microenvironment, <u>it modulates the inhibitory retro-control of steroids by interfering with ER in diverse targets, mainly the pituitary gland (LH, FSH production), preoptic area (libido), and the Leydig cell (testosterone production), recreating a balance between LH, FSH, T, and estrogen</u> [18].</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Conclusions</strong></p><p><strong></strong></p><p><strong><em>CC is a compelling option to treat male hypogonadism, although a chronic treatment is needed in most patients. <u>About one in every four patients respond to a CC short trial to "reboot" the HPT axis physiology</u>. Further understanding of TT kinetics in these patients in the long term is warranted.</em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em>Look over the CC/EC threads in post #7</em></strong></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/clomiphene-citrate-a-potential-alternative-for-tth-in-hypogonadal-males.27343/[/URL]</p><p></p><p></p><p></p><p><strong><em>Pulled a few out for you!</em></strong></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/a-paradoxical-decline-in-semen-parameters-in-men-treated-with-clomiphene-citrate-clomid.22076/[/URL]</p><p></p><p><strong>5 | CONCLUSION</strong></p><p></p><p><em><strong>Treatment with clomiphene citrate can be <u>associated with a decrease in semen count, concentration, motility, morphology, and total motile sperm count in up to 20% of patients</u>. <u>Among men who had a decline in semen parameters, 17% of them may not recover following discontinuation of therapy</u>. The benefits of therapy should be weighed against potential negative impacts on fertility, and close follow-up should be maintained. <u>More studies should report on the decline in semen parameters so the magnitude of this effect can be more easily measured by reproductive specialists in the future</u>.</strong></em></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/clomid-clomiphene-citrate-treatment-may-take-up-to-9-months-to-show-max-sperm-response.25263/[/URL]</p><p></p><p><strong>Conclusions</strong></p><p><strong></strong></p><p><strong><em>In men prescribed CC for fertility optimization, <u>we observed a maximal improvement in TT at 6 months, followed by a plateau</u>. <u>Sperm concentrations showed a statistically significant improvement at 9 months</u>. <u>Our results suggest that a longer duration of CC therapy may be needed to fully appreciate the benefit of CC treatment</u>. Our study is limited by retrospective analysis, absence of controls, and small sample size. Work is underway to examine long-term follow-up data of CC in men seeking treatment for hypogonadism rather than optimization of fertility.</em></strong></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/clomiphene-may-take-9-months-to-fully-restore-sperm-count.25587/[/URL]</p><p></p><p><strong>CONCLUSIONS</strong></p><p><strong></strong></p><p><strong><em>Overall, our study raises the question of what a suitable endpoint may be when studying CC monotherapy in the context of male subfertility and hypogonadism. <u>We pose that 6 months of CC may be needed to achieve maximal benefit in TT while 9 months may be necessary to observe statistical benefit in sperm concentration</u>. The findings from this work may serve as additional data for reproductive urologists to use to counsel men regarding the potential benefits of CC monotherapy for subfertility.</em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em>Look over post #22</em></strong></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/hypogonadism-101.27657/page-2[/URL]</p><p></p><p></p><p><strong><em>Everything you ever wanted to know about Natesto!</em></strong></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/comparing-rates-of-polycythemia-in-hypogonadal-men-using-nasal-t-gel-versus-im-tc.26063/#post-233737[/URL]</p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/natesto-lost-effects-quickly-nasal-test.28148/#post-260503[/URL]</p><p></p><p></p><p></p><p></p><p><strong><em>Some more insight CC/Natesto!</em></strong></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/clomiphene-to-natesto-results.22400/[/URL]</p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/men-converting-from-cc-to-natesto-with-a-desire-to-maintain-spermatogenesis-should-be-followed-closely.24043/[/URL]</p></blockquote><p></p>
[QUOTE="madman, post: 267306, member: 13851"] Chances are slim, especially at your age. Both would be used for the long-term as T levels will go back to baseline when you stop. There is a small percentage of men who may respond to a short trial of clomiphene citrate to reboot the HPTA. Younger men tended to do better. Even then long-term high-quality RCTs on clomid/rebooting the HPTA are lacking. Most giving clomid/hCG mono a go ends up jumping on TRT in the long run. Key points here: [B][I]*We hypothesize that [U]MH is a chronic irreversible condition in most cases, but in a selected group of patients[/U], which Devoto and Aravena call mild hypothalamic dysfunction, [U]a trial with CC could reboot the HPT axis[/U] *Our study has some limitations worth discussing. [U]About 40% of the subjects initially screened did not finish the follow-up and were excluded, of whom 40% kept symptomatic and 60% elected to change to testosterone therapy[/U]; however, this represents the real-life challenges that must be accounted for *Based on current results, [U]one in every four hypogonadal men with normal testicles may respond to a short trial of CC to "reboot" the HPT axis, with the potential for physiology maintenance, avoiding chronic treatment. Responders tend to be younger patients[/U][/I] *[I]CC is a compelling option to treat male hypogonadism, [U]although a chronic treatment is needed in most patients[/U]. [U]About one in every four patients respond to a CC short trial to "reboot" the HPT axis physiology[/U]. [U]Further understanding of TT kinetics in these patients in the long term is warranted[/U][/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/clomid-monotherapy-to-treat-male-hypogonadism-chronic-treatment-is-needed-in-most-patients.25319/[/URL] [B][I]*The main objective of our study was to elucidate which percentage of MH reversed by a 40-day CC treatment can sustain physiological TT levels in the midterm since scarce studies analyzed the kinetics of TT after stopping CC treatment.[/I][/B] [I]Kaminetsky et al. reported that in patients with secondary hypogonadism who responded to enclomiphene citrate therapy, once the treatment was stopped, TT levels decreased and returned to the pre-treatment values [11]. The same happened in the Marconi et al. study, which reported decreased TT levels 3 months after discontinuation of CC treatment, 78% under the normal range. The six cases in which TT was in the normal range 3 months after CC discontinuation also dropped TT levels (to pre-treatment levels) 6 months after ending treatment [4]. Devoto and Aravena reported contrasting results in a subgroup of patients with functional hypogonadotropic hypogonadism who respond to CC therapy by maintaining normal TT levels 6 months after ending treatment [12]. Our study partially agreed with their data; 18 patients (24%) maintained asymptomatic and with TT levels over 300 ng/dl after 6 months of stopping the treatment, against the 12/16 (75%) of Devoto. This conflict could be due to the study draw since they just analyzed the patients who responded to a 10-day trial with CC and used a 6-month CC therapy. [B]We hypothesize that MH is a chronic irreversible condition in most cases, but in a selected group of patients, which Devoto and Aravena call mild hypothalamic dysfunction, a trial with CC could reboot the HPT axis. On behalf of drug safety and side effects, a long-term follow-up cohort demonstrates that CC is an oral therapy with durable efficacy and a favorable side effect profile in the long term up to 7 years. [/B]Only 36 men (9%) reported side effects in that cohort, the most common side effects were consistent with those reported in prescribing information.[B] However, patients and providers should also be aware of the progressive need to monitor for symptoms of hyperestrogenemia while on sustained CC therapy [10]. Molecular studies show that CC is composed of two very different isomers, [U]enclomiphene (EC), the trans-isomer (62%), and zuclomiphene, the cis-isomer (38%)[/U]—with potentially opposing effects. The first isomer has an estrogen antagonist effect, by preventing estrogen receptor-mediated negative feedback at the level of the pituitary and hypothalamus, while zuclomiphene acts as an estrogen agonist [13]. [U]The trans-isomer is a very promising drug for MH, appearing to be responsible for the desired anti-estrogen effect of CC, offering significant elevations in T levels[/U] [11, 14]. This could result in the correction of testosterone levels and hypogonadal symptoms without suppressing spermatogenesis.[U] In addition to the benefits mentioned above, enclomiphene lacks the estrogen receptor agonist activity seen with clomiphene citrate caused by the cisisomer zuclomiphene, which accumulates in the body and can take more than 6 months to be eliminated after discontinuation of treatment[/U].[/B] [B][U]This may mitigate some of the estrogenic side effects that some men can present and increase the potential beneficial effects[/U] [14, 15]. Unfortunately, due to the difficulty inherent in getting a new molecular entity approved by the FDA, the future of enclomiphene looks bleak at best [16]. *Our study has some limitations worth discussing. About 40% of the subjects initially screened did not finish the follow-up and were excluded, of whom 40% kept symptomatic and 60% elected to change to testosterone therapy; however, this represents the real-life challenges that must be accounted for. [U]Based on current results, one in every four hypogonadal men with normal testicles may respond to a short trial of CC to "reboot" the HPT axis, with the potential for physiology maintenance, avoiding chronic treatment[/U]. [U]Responders tend to be younger patients[/U][/B]. Baseline gonadotropins were not strong predictors of CC treatment response in hypogonadal men [2], thus not evaluated in our study.[/I] [B][I]A recent meta-analysis comprising 17 studies (four randomized controlled trials), with a total of 1279 patients has shown significant hormones, semen, and symptoms improvement in hypogonadal men during CC treatment, with<10% adverse events reported (none serious) [17]; [U]however, more extensive prospective trials are needed to understand further the durability of the hormonal response to CC with time[/U].[/I][/B] [I][B]While little is known about CC’s effect on the intercellular signaling and testicular microenvironment, [U]it modulates the inhibitory retro-control of steroids by interfering with ER in diverse targets, mainly the pituitary gland (LH, FSH production), preoptic area (libido), and the Leydig cell (testosterone production), recreating a balance between LH, FSH, T, and estrogen[/U] [18].[/B][/I] [B]Conclusions [I]CC is a compelling option to treat male hypogonadism, although a chronic treatment is needed in most patients. [U]About one in every four patients respond to a CC short trial to "reboot" the HPT axis physiology[/U]. Further understanding of TT kinetics in these patients in the long term is warranted. Look over the CC/EC threads in post #7[/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/clomiphene-citrate-a-potential-alternative-for-tth-in-hypogonadal-males.27343/[/URL] [B][I]Pulled a few out for you![/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/a-paradoxical-decline-in-semen-parameters-in-men-treated-with-clomiphene-citrate-clomid.22076/[/URL] [B]5 | CONCLUSION[/B] [I][B]Treatment with clomiphene citrate can be [U]associated with a decrease in semen count, concentration, motility, morphology, and total motile sperm count in up to 20% of patients[/U]. [U]Among men who had a decline in semen parameters, 17% of them may not recover following discontinuation of therapy[/U]. The benefits of therapy should be weighed against potential negative impacts on fertility, and close follow-up should be maintained. [U]More studies should report on the decline in semen parameters so the magnitude of this effect can be more easily measured by reproductive specialists in the future[/U].[/B][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/clomid-clomiphene-citrate-treatment-may-take-up-to-9-months-to-show-max-sperm-response.25263/[/URL] [B]Conclusions [I]In men prescribed CC for fertility optimization, [U]we observed a maximal improvement in TT at 6 months, followed by a plateau[/U]. [U]Sperm concentrations showed a statistically significant improvement at 9 months[/U]. [U]Our results suggest that a longer duration of CC therapy may be needed to fully appreciate the benefit of CC treatment[/U]. Our study is limited by retrospective analysis, absence of controls, and small sample size. Work is underway to examine long-term follow-up data of CC in men seeking treatment for hypogonadism rather than optimization of fertility.[/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/clomiphene-may-take-9-months-to-fully-restore-sperm-count.25587/[/URL] [B]CONCLUSIONS [I]Overall, our study raises the question of what a suitable endpoint may be when studying CC monotherapy in the context of male subfertility and hypogonadism. [U]We pose that 6 months of CC may be needed to achieve maximal benefit in TT while 9 months may be necessary to observe statistical benefit in sperm concentration[/U]. The findings from this work may serve as additional data for reproductive urologists to use to counsel men regarding the potential benefits of CC monotherapy for subfertility. Look over post #22[/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/hypogonadism-101.27657/page-2[/URL] [B][I]Everything you ever wanted to know about Natesto![/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/comparing-rates-of-polycythemia-in-hypogonadal-men-using-nasal-t-gel-versus-im-tc.26063/#post-233737[/URL] [URL unfurl="true"]https://www.excelmale.com/forum/threads/natesto-lost-effects-quickly-nasal-test.28148/#post-260503[/URL] [B][I]Some more insight CC/Natesto![/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/clomiphene-to-natesto-results.22400/[/URL] [URL unfurl="true"]https://www.excelmale.com/forum/threads/men-converting-from-cc-to-natesto-with-a-desire-to-maintain-spermatogenesis-should-be-followed-closely.24043/[/URL] [/QUOTE]
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